(+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-c] pyridine-5 (4-H)-acetic acid methyl ester known as clopidogrel under the International Non-Proprietry Name is marketed as hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and antithrombotic properties and finds medicinal applications in this field. It can be represented by Formula-I, and was disclosed in U.S. Pat. No. 4,529,596 (hereinafter referred as ‘596’ patent) in its racemic form for the first time.

The ‘596’ patent provides a synthesis of said molecule of Formula I by the reaction of a thienopyridine derivative of Formula II with a chloro compound of Formula III (where X═Cl) in solvents like dimethyl formamide, alcohols and ethyl acetate in presence of alkali metal carbonates. However, it does not suggest preparation/source of the starting material, tetrahydrothienopyridine derivative, of Formula II.

In a subsequent patent, JP 63101385, a convenient process for the preparation of the 4,5,6,7-tetrahydrothieno (3,2-c) pyridine intermediate (Formula II) was disclosed. According to the multi-step process of this patent, a commercially available 2-(2-thienyl)-ethylamine (Formula IV) was reacted with formaldehyde to give an intermediate 1,3,5-tris-(2-thienylethyl)-hexahydro-S-triazine which was isolated and treated with HCl in polar solvents to give the 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II.
A similar process was disclosed in U.S. Pat. No. 5,132,435 for the preparation of Clopidogrel by using the same reactants per se to yield the 4,5,6,7-tetrahydrothieno (3,2-c) pyridine derivative (Formula II) and reacting the same with a bromo-derivative of Formula III (X═Br) in solvents selected from alcoholic solvents, DMF, ether solvents and ethyl acetate in presence of alkali metal carbonate as the base. In the process, 2-(2-thienyl) ethylamine was reacted with formalin solution in water by heating to a temperature range of 70° C. to 90° C. and isolated the 2-(2-thienyl)-ethyl formimine by a long procedure in pure form. This was reacted with dry hydrochloric acid solution in dimethylformamide to form the cyclized product (Formula II).
In these processes the reactants per se are same but employ varying conditions to achieve better purity or yield. Although some of the problems are solved by modifying the reaction conditions or route of synthesis as taught by the prior art, there still exist problems like polymerization of intermediates which need to be investigated.
The cyclisation of the intermediate 2-(2-thienyl)-ethyl formimine does not take place in presence of water. If water is present in the reaction it necessitates the isolation of formimine intermediate in pure form. This increases the number of operations and makes process plant unfriendly from industrial scale-up point of view. Moreover, the isolated intermediate, 2-(2-thienyl) ethyl formimine, is not a stable compound and polymerizes to give a trimer which makes it difficult to store/handle in normal conditions.
Although, the reaction of bromo-compound (Formula III) with 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II gave moderate yields in the reported processes, the reactions takes long time for completion at temperature 60° C. to 90° C. as reported in ‘435’ patent.
Carrying out reactions at above temperatures, that too for longer period, lead to formation of various impurities due to the lack of selectivity of reactions or decomposition of the reactants or products, which necessitates extra purification resulting into yield losses and increase in number of operations not desirable for a practical process. The search for a manufacturing process for the preparation of Clopidogrel employing easy synthetic methods resulting in a satisfactory yield/purity of final product remains undoubtedly of interest.
The pure enantiomeric forms of clopidogrel (dextro and levo isomers) was disclosed in EP 281459 which teaches the isolation of the dextro rotatory isomer of Clopidogrel by diasteriomeric salt formation of racemic Clopidogrel base using an optically active acid such as 10-L-camphor sulfonic acid in solvents like acetone, followed by successive recrystallization of the salt until a product with constant rotatory power was obtained. The pure dextrorotatory isomer of clopidogrel ( herein after referred as clopidogrel free base) was released from the respective diasteriomeric salt by reaction with a base.
But in practice, the diasteriomeric salt that separates out was filtered, and purified by refluxing, cooling and filtration from acetone results in low yield of the dextro isomer (55%). The process of purification in acetone is repeated several times for obtaining the desired purity of diasteriomeric salt. The chiral purity of the dextroisomer is low (96%) even after the repeated crystallization.
The Clopidogrel free base was then converted into its hydrogen sulfate salt by dissolving in acetone, cooling and mixing with concentrated sulfuric acid to precipitation. The precipitate thus obtained is then isolated by filtration, washed and dried to give Clopidogrel hydrogen sulfate in the form of white crystals whose melting point was 184° C. and optical rotation was +55.1° (c=1.891/CH3OH). But '459 patent did not characterize or suggest any name to this crystals (polymorph) of Clopidogrel hydrogen sulfate.
Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorph forms of Clopidogrel hydrogen sulfate referred to as Form-I and Form-II. The '915 patent identified that the precipitation method described in '459 patent had led to crystalline Form-I. The '915 also deals with a new crystalline form called Form-II of Clopidogrel hydrogen sulfate. The latter is suggested to be thermodynamically most stable crystalline form. According to '915 patent both polymorphs, namely Form I and Form II, were prepared from the same solvent viz; acetone.
The process for obtaining crystalline Form-II of Clopidogrel hydrogen sulfate according to example 1A of the '915 patent describes the introduction of Clopidogrel camphor sulfate in MDC and transformation of salt into the base with potassium carbonate solution. Clopidogrel base is extracted in MDC and evaporated. Residue obtained is dissolved in acetone and cooled. Addition of sulfuric acid precipitated out Clopidogrel hydrogen sulfate. Also in the same application it was described to get Form-II either by keeping mother liquor of Form-I or by heating acetone solution containing the base after addition of sulfuric acid to reflux or by subjecting the suspension to mechanical shearing using a shearing device or by inoculation.
However, this process was not suitable for the production of Form I of clopidogrel hydrogen sulphate on an industrial scale owing to its thermodynamic instability in solvents like acetone and invariably yielded Form II without having the need of keeping for longer periods (ref. '915 patent). This problem became the subject of the patent application WO 2004020443 (herein after referred as '443 patent).
According to the '443 patent application, a process was claimed to produce Form I consistently by forming hydrogen sulphate salt of clopidogrel from a solvent selected from the series of C1-C5 alcohols or their esters with C1-C4 acids, optionally of mixture of alcohols and esters. The process involves dissolving clopidogrel base in solvents like isopropyl alcohol and/or butyl acetate, cooling the mixture, adding sulfuric acid and inoculating the mixture with Form-I of Clopidogrel hydrogen sulfate. Stirring the crystallized mixture precisely at a temperature between −5 and +15° C. to get crystals of clopidogrel in Form-I. In another process variant, the subject of '443 patent, the clopidogrel hydrogen sulphate was directly dissolved at reflux in the above mentioned solvents and crystallized under cooling.
Although the process mentioned in the '443 patent application works in butyl acetate, which is known to have hazardous properties (affects central nervous system and exposure limit is 150 ppm), but fails to give pure Form I in other industrially friendly solvents like ethyl acetate under the specified conditions. As the Form I is thermodynamically unstable, the process variant of dissolving clopidogrel hydrogen sulphate salt in solvents at higher temperature and cooling to precipitate Form I resulted in Form II or Form IV or their mixture with Form I.
This finding is in agreement with the prior art disclosed in United States patent application 2003/0225129 A2 (herein after referred as '129 patent), where isopropanol was used to produce Form-IV crystals (Form IV of clopidogrel hydrogen sulphate is known to be its isopropyl alcohol solvate) by a process comprising the steps of preparing solution of Clopidogrel hydrogen sulfate either by using Clopidogrel base or its hydrogen sulfate salt in isopropyl alcohol at reflux and cooling to precipitate Clopidogrel hydrogen sulfate and separating the mentioned polymorph, i.e. Form IV.
The '129 patent also describes process for the preparation of Form-II from solvents selected from dichloromethane, 1,4-dioxane, toluene, chloroform, ethyl acetate, methyl ethyl ketone and t-butyl methyl ether. The '129 patent, for the first time, claimed to produce Form II from ethyl acetate which was the main subject of '443 patent application.
Moreover, in our hands under the specified conditions at lower temperature of −5° to 15° C., as claimed in the '443 patent, we found the crystals formed in ethyl acetate is Form II of clopidogrel hydrogen sulphate.
It is clear from above discussion that same solvent gives two different crystalline forms under different experimental conditions.
So, it is evident from the prior art that methods to produce Form-I of clopidogrel hydrogen sulphate from different solvents are poorly reproducible, necessitating the optimization of experimental conditions other than of the selection of solvents. Since Form-I is kinetically controlled and Form-II is thermodynamically controlled form, they require very specific temperature range and specific conditions for getting reproducible results. Also, a minor variation in condition appears to give Form-II instead of expected Form-I or a mixture of Form-I & Form-II. Since, Form I of clopidogrel hydrogen sulphate is used for pharmaceutical formulation, the importance of a rugged method that gives Form I consistently doesn't require any emphasis.
Apart from the inconsistency of the process in solvents like ethyl acetate, the process given in the '443 patent application also suffers from operational problems from an industrial scale-up point of view as follows;    1. During the salt formation in solvents like ethyl acetate at lower temperature, the product forms a sticky & lumpy mass that sticks to the stirrer and difficult to disperse due to the lowered solubility at this condition,    2. The workability of the process found limit to single solvent mainly butyl acetate which is a hazardous and industrially unfriendly,    3. The crystal form obtained by performing the salt formation between 5° to 15° C. in ethyl acetate is Form II of clopidogrel hydrogen sulphate. This may be due to the non-dispersability of the sticky mass obtained under these conditions and the fast/prolonged stirring performed for dispersion, allows the crystals to grow and rearranges to the most stable form.
Thus there is a need to get industrially reliable process for the preparation of Form-I and Form-II without contamination of one into other Form. So it was of interest to find a suitable solvent where the crystallization can be performed at a temperature near to ambient temperature, for solving the inconsistency/operational problems in the prior art, yielding clopidogrel Form I in its pure state. Also of interest was to see its workability at higher temperature to affect a fast and easily dispersible crystallization conditions, an important factor for operations.